This R21 proposal is for funding to determine whether structural and functional changes in the brain white matter pathways that connect frontal and temporal cortices are significantly different in people who are at genetic high risk for developing schizophrenia compared with low risk controls and to determine whether these measures can eventually distinguish those who go on to have symptoms from those who do not. We thus hypothesize that the neurodevelopmental basis for schizophrenia is disturbance in the white matter pathways involved in processing language and related functions, and that these changes will be detectable by MRI in significantly more well individuals that are at genetic risk for developing the illness than in those who are not. In order to test this hypothesis, we aim to evaluate a large cohort of individuals (N=60) who have an increased familial risk for developing schizophrenia and compare them to an age, sex, and social class proportionally matched group of controls (N=30). The integrity of white matter in regions that connect the temporal and frontal lobes (uncinate, arcuate, inferior longitudinal, inferior occipito-frontal fasciculi) will be determined using a Diffusion Tensor Imaging Protocol (DTI). Evidence of anomalous activation within the above brain regions and pathways will be solicited directly by fMRI using a lexical decision task previously shown to differentiate people with schizophrenia and people at high-risk for schizophrenia from controls. The correlation of structural change with functional change will provide an understanding of the significance of any structural abnormalities. Since considerably more individuals in a genetically at risk cohort are likely to develop schizophrenia sometime in the future, the deficits determined to be present in this current study may be later found to be biological markers for whom among high-risk individuals are likely to develop schizophrenia and thus be valuable for decisions about early intervention. PUBLIC HEALTH RELEVANCE This is an R21 application for funding to ascertain a genetically at high-risk cohort for schizophrenia (N=60) and compare them to low-risk controls on deficits in the integrity of brain frontal and temporal lobe white matter pathways and their functioning. MRI scans will be performed over 2 years to determine brain imaging measures that can be used in future studies to distinguish those individuals who are destined to develop schizophrenia from those who do not before the onset of illness.